1. Field of the Invention
The present invention relates to a novel immunomodulator. More specifically, the present invention relates to an immunomodulator (e.g., immunoenhancer and immunosuppressant) capable of oral intake which has a novel suppressive function on macrophages (hereinafter sometimes abbreviated as "M.PHI." ) or monocytes and which may be used, for example, for the treatment, improvement and prevention of human immunological diseases such as hepatic cirrhosis, hepatitis, diabetes, gastrointestinal inflammatory diseases such as inflammatory bowel diseases (ulcerative colitis, Crohn disease, etc.), auto-immune diseases and allergic diseases such as hypersensitive interstitial pneumonia, pulmonary fibrosis, chronic rheumatoid arthritis, asthma and cutaneous atopy, and cancers, and to a drug, a food (including a food for medical care, a health food or a special sanitary food), a nutrient and an infusion containing the same.
2. Description of the Related Art
As used herein, the term immune system refers to a system in an organism for defending itself from exogenous infection with virus, bacteria or the like, or from invasion of a human body with transformed cells (tumor cells and the like) formed by transformation of autologous cells. However, the immune system occasionally behaves abnormally, i.e., it functions excessively and acts to reject autologous components, or, on the other hand it sometimes functions deficiently, resulting in an immunocompromised state. Diseases resulting from these abnormal responses are generally called immunological diseases. Examples thereof include diverse diseases, for example, acute or chronic inflammatory diseases such as atopic cutaneous inflammatory diseases, pollinosis, asthma and sarcoidosis; autoimmune diseases such as allergic diseases, chronic rheumatoid arthritis, diabetes (IDDM), SLE and chronic fatigue syndrome; hepatitis, hepatic cirrhosis, inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn disease; and cancer cachexia. These immunological diseases originate from complex pathological causes. Systemic immunodeficiency and functional deficiency originate from pathological inflammation accompanied by cell proliferation, differentiation or cell necrosis through local production of cytokines or inflammatory mediators.
As cells that participate in immunity, T lymphocytes and B lymphocytes are well known. These cells exhibit a wide variety of functions as cells playing roles in cellular immunity and humoral immunity respectively. Meanwhile, macrophages and monocytes are cells that are intimately involved in both cellular immunity and humoral immunity, and they participate significantly in rejection of non-self foreign bodies, for example, in immunological diseases such as allergy and rheumatism, cancers and bacterial infection.
The functions of macrophages and monocytes are classified into four different types, a secretary function, an immunoregulatory function (mainly antigen presentation), treatment of foreign bodies and waste matters, a phagocytic function and a cytotoxic/cytostatic activity against target cells. It is widely accepted that these cells produce diverse inflammatory mediators; for example cytokines such as TNF, IL-12, IL-1, IL-6, TGF.beta. and IL-8 and so on; hormonal molecules such as neopterine (NPT) and dihydroxyepiandrosterone (DHEA); arachidonic acid metabolites such as PGE2 and LTB4; complement and related molecules such as C5a and C3; such as reactive oxygen and reactive nitrogen intermediates. It has not been clarified whether these diverse functions are exhibited by one kind of macrophage or monocyte or by distinctive groups of macrophages or monocytes having different functions. While lymphocytes are classified into distinctive subsets according to their cell surface markers and the distinctive functional markers uniquely correspond to each subset of lymphocyte, the correspondence between the wide variety of functions of macrophages is less clear. Monocytes have not been classified into cellular subsets. For this reason, although macrophages and monocytes play quite important roles in the triggering and the pathological progression of the above mentioned inflammatory, allergic and immunological diseases, the functional classification of macrophages and monocytes subsets has not yet been applied at all to therapeutic, prophylactic and preventive treatment of human diseases, with the assumption of the presence of macrophage and monocyte subsets, and even the hypothesis thereof has not yet been given.
In recent years, in the patients suffering from allergic diseases, autoimmune-diseases such as chronic rheumatoid arthritis and cancer, the inclination of helper T cell subsets in the peripheral blood has been pointed out and has been linked to the pathology of these diseases. Helper T lymphocytes which are a subset of T lymphocytes have been further classified into two subsets, namely Th1 and Th2, and it is currently proving that the ratio of these two types is an relevant index of immunological functions of patients. Attempts are being made to establish a more appropriate therapeutic treatment by diagnosis of the ratio or by improvement of the ratio based on this index. That is, it is known that when the amount of Th2 inducing IgE production from B cells is higher than that of Th1 (Th1&lt;Th2), allergic diseases are worsened. Attempts are being made to suppress allergy upon measuring a Th1/Th2 ratio to examine an immunological response of patients or to provide Th1 response superior to Th2 responses. On the contrary, the presence of diseases caused by a predominance of Th1 has been successively indicated also in chronic rheumatoid arthritis or an asthmatic inflammatory disease at the chronic stage.
Even when the Th1/Th2 balance is measured using biological materials and the functions of the two subsets are modulated, this modulation has not successfully been utilized currently in the examination or the diagnosis of local chronic inflammatory diseases or allergic diseases. The terms such as Th1 diseases and Th2 diseases have been used lately. However, these terms cannot necessarily be distinguished clearly.
The Th1/Th2 presence ratio is only an index of lymphocyte subsets. Since the in vivo dynamism of the lymphocyte subsets is actually regulated by the cell group called accessory cells including macrophages in the present invention, it is difficult to appropriately diagnose the progression of diseases with only the Th1/Th2 presence ratio and to treat the same on the basis of this index. As will be described below, the Th1/Th2 balance is controlled by the distinct macrophage/monocytes functions. Even if a skewing to Th1&gt;Th2 is intended, this is hardly effective for therapy of immunological diseases, due to the presence of a complex cytokine network, and a new index for diagnosis and therapy has been in demand.
It has been clarified that in macrophages participating in the inflammatory reactions, the functions of the cells are variable depending on environmental factors such as oxidative stress, cytokine stimulation, infection with virus or bacteria and the like. However, the correspondence between the functions and the classification of cell subsets of macrophages is highly uncertain. New findings are required in the above-mentioned classification of functions and subsets, and these findings will lead to the development of quite useful new therapeutic methods. Under such circumstances, the development of excellent agents for modulating immunity, namely, immunomodulators, has been in demand.